desvenlafaxine 50 MG (as desvenlafaxine succinate 76 MG) 24 HR Extended Release Oral Tablet
Generic Name: DESVENLAFAXINE SUCCINATE
Brand Name: Pristiq Extended-Release
- Substance Name(s):
- DESVENLAFAXINE SUCCINATE
7 7.1 Drugs Having Clinically Important Interactions with PRISTIQ Table 8: Clinically Important Drug Interactions with PRISTIQ Monoamine Oxidase Inhibitors (MAOI) Clinical Impact The concomitant use of SSRIs and SNRIs including PRISTIQ with MAOIs increases the risk of serotonin syndrome.
Intervention Concomitant use of PRISTIQ is contraindicated: With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with PRISTIQ.
Within 14 days of stopping an MAOI intended to treat psychiatric disorders.
In a patient who is being treated with linezolid or intravenous methylene blue.
[see Dosage and Administration (2.7) , Contraindications (4) and Warnings and Precautions (5.2) ].
Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact Concomitant use of PRISTIQ with other serotonergic drugs increases the risk of serotonin syndrome.
Intervention Monitor for symptoms of serotonin syndrome when PRISTIQ is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems.
If serotonin syndrome occurs, consider discontinuation of PRISTIQ and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2) ].
Examples other SNRIs, SSRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St.
John’s Wort Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of PRISTIQ with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding.
This may be due to the effect of PRISTIQ on the release of serotonin by platelets.
Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when PRISTIQ is initiated or discontinued [see Warnings and Precautions (5.4) ] .
Examples NSAIDs, aspirin, and warfarin Drugs that are Primarily Metabolized by CYP2D6 Clinical Impact Concomitant use of PRISTIQ increases C max and AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug [see Clinical Pharmacology (12.3) ] .
Intervention Original dose should be taken when co-administered with PRISTIQ 100 mg or lower.
Reduce the dose of these drugs by up to one-half if co-administered with 400 mg of PRISTIQ.
Examples desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine 7.2 Drugs Having No Clinically Important Interactions with PRISTIQ Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with PRISTIQ [see Clinical Pharmacology (12.3) ].
7.3 Alcohol A clinical study has shown that PRISTIQ does not increase the impairment of mental and motor skills caused by ethanol.
However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking PRISTIQ.
7.4 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine.
This is due to lack of specificity of the screening tests.
False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.
10 10.1 Human Experience with Overdosage There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans.
However, desvenlafaxine (PRISTIQ) is the major active metabolite of venlafaxine.
Overdose experience reported with venlafaxine (the parent drug of PRISTIQ) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert.
In postmarketing experience, overdose with venlafaxine (the parent drug of PRISTIQ) has occurred predominantly in combination with alcohol and/or other drugs.
The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting.
Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.
Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants.
Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients.
The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear.
10.2 Management of Overdosage No specific antidotes for PRISTIQ are known.
In managing over dosage, consider the possibility of multiple drug involvement.
In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.
11 PRISTIQ is an extended-release tablet for oral administration that contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD.
Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication used to treat major depressive disorder.
Desvenlafaxine is designated RS -4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the empirical formula of C 16 H 25 NO 2 (free base) and C 16 H 25 NO 2 ∙C 4 H 6 O 4 ∙H 2 O (succinate monohydrate).
Desvenlafaxine succinate monohydrate has a molecular weight of 399.48.
The structural formula is shown below.
Desvenlafaxine succinate is a white to off-white powder that is soluble in water.
The solubility of desvenlafaxine succinate is pH dependent.
Its octanol:aqueous system (at pH 7.0) partition coefficient is 0.21.
PRISTIQ is formulated as an extended-release tablet for once-a-day oral administration.
Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively.
Inactive ingredients for the 25 mg tablet consist of hypromellose, microcrystalline cellulose, talc, magnesium stearate, a film coating which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and iron oxides.
Inactive ingredients for the 50 mg tablet consist of hypromellose, microcrystalline cellulose, talc, magnesium stearate and film coating, which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and iron oxides.
Inactive ingredients for the 100 mg tablet consist of hypromellose, microcrystalline cellulose, talc, magnesium stearate and film coating, which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, iron oxide and FD&C yellow #6.
14 Major Depressive Disorder The efficacy of PRISTIQ as a treatment for depression was established in four 8-week, randomized, double-blind, placebo-controlled, fixed-dose studies (at doses of 50 mg per day to 400 mg per day) in adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder.
In the first study, patients received 100 mg (n = 114), 200 mg (n = 116), or 400 mg (n = 113) of PRISTIQ once daily, or placebo (n = 118).
In a second study, patients received either 200 mg (n = 121) or 400 mg (n = 124) of PRISTIQ once daily, or placebo (n = 124).
In two additional studies, patients received 50 mg (n = 150 and n = 164) or 100 mg (n = 147 and n = 158) of PRISTIQ once daily, or placebo (n = 150 and n = 161).
PRISTIQ showed superiority over placebo as measured by improvement in the 17-item Hamilton Rating Scale for Depression (HAM-D 17 ) total score in four studies and overall improvement, as measured by the Clinical Global Impressions Scale – Improvement (CGI-I), in three of the four studies.
In studies directly comparing 50 mg per day and 100 mg per day there was no suggestion of a greater effect with the higher dose and adverse reactions and discontinuations were more frequent at higher doses [see Dosage and Administration (2.1) ] .
Table 9: Primary Efficacy (HAM-D 17 ) Results for Short-term Studies PRISTIQ Study No.
Primary Endpoint: HAM-D 17 Placebo 50 mg/day 100 mg/day 200 mg/day 400 mg/day 1 Baseline Score (SD Standard deviation; ) 23.1 (2.5) 23.2 (2.5) 22.9 (2.4) 23.0 (2.2) Difference from Placebo (95% CI Difference between least squares means at final evaluation, calculated as drug response minus placebo response; unadjusted 95% confidence intervals ) -2.9 Adjusted p-value < 0.05; (-5.1, -0.8) -2.0 -3.1 (-5.2, -0.9) 2 Baseline Score (SD ) 25.3 (3.3) 24.8 (2.9) 25.2 (3.2) Difference from Placebo (95% CI ) -3.3 (-5.3, -1.2) -2.8 (-4.8, -0.7) 3 Baseline Score (SD ) 23.0 (2.6) 23.4 (2.6) 23.4 (2.6) Difference from Placebo (95% CI ) -1.9 (-3.5, -0.3) -1.5 4 Baseline Score (SD ) 24.3 (2.6) 24.3 (2.4) 24.4 (2.7) Difference from Placebo (95% CI ) -2.5 (-4.1, -0.9) -3.0 (-4.7, -1.4) Analyses of the relationships between treatment outcome and age and treatment outcome and gender did not suggest any differential responsiveness on the basis of these patient characteristics.
There was insufficient information to determine the effect of race on outcome in these studies.
In a longer-term trial (Study 5), adult outpatients meeting DSM-IV criteria for major depressive disorder, who responded to 8 weeks of open-label acute treatment with 50 mg per day desvenlafaxine and subsequently remained stable for 12 weeks on desvenlafaxine, were assigned randomly in a double-blind manner to remain on active treatment or switch to placebo for up to 26 weeks of observation for relapse.
Response during the open-label phase was defined as a HAM-D 17 total score of ≤ 11 and CGI-I ≤ 2 at the day 56 evaluation; stability was defined as HAM-D 17 total score of ≤ 11 and CGI-I ≤ 2 at week 20 and not having a HAM-D 17 total score of ≥ 16 or a CGI-I score ≥ 4 at any office visit.
Relapse during the double-blind phase was defined as follows: (1) a HAM-D 17 total score of ≥ 16 at any office visit, (2) discontinuation for unsatisfactory efficacy response, (3) hospitalized for depression, (4) suicide attempt, or (5) suicide.
Patients receiving continued desvenlafaxine treatment experienced statistically significantly longer time to relapse compared with placebo.
At 26 weeks, the Kaplan-Meier estimated proportion of relapse was 14% with desvenlafaxine treatment versus 30% with placebo.
Estimated Proportion of Relapses vs.
Number of Days since Randomization (Study 5) In another longer-term trial (Study 6), adult outpatients meeting DSM-IV criteria for major depressive disorder and who responded to 12 weeks of acute treatment with desvenlafaxine were assigned randomly to the same dose (200 or 400 mg per day) they had received during acute treatment or to placebo for up to 26 weeks of observation for relapse.
Response during the open-label phase was defined as a HAM-D 17 total score of ≤ 11 at the day 84 evaluation.
Relapse during the double-blind phase was defined as follows: (1) a HAM-D 17 total score of ≥ 16 at any office visit, (2) a CGI-I score of ≥ 6 (versus day 84) at any office visit, or (3) discontinuation from the trial due to unsatisfactory response.
Patients receiving continued desvenlafaxine treatment experienced statistically significantly longer time to relapse over the subsequent 26 weeks compared with those receiving placebo.
At 26 weeks, the Kaplan-Meier estimated proportion of relapse was 29% with desvenlafaxine treatment versus 49% with placebo.
Estimated Proportion of Relapses vs.
Number of Days since Randomization (Study 6) In a postmarketing study, the efficacy of PRISTIQ at a dose lower than 50 mg per day was evaluated in an 8-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study in adult outpatients with Major Depressive Disorder.
The treatment arms were 25 mg (n=232), 50 mg (n=236), and placebo (n=231).
The 50 mg dose was superior to placebo, as measured by the mean change from baseline on the HAMD-17.
The 25 mg dose was not superior to placebo.
Figure 4 Figure 5
16 /STORAGE AND HANDLING PRISTIQ ® (desvenlafaxine) extended-release tablets are available as follows: 25 mg, tan, square pyramid tablet debossed with “W” (over) “25” on the flat side NDC 0008-1210-30, bottle of 30 tablets in unit-of-use package 50 mg, light pink, square pyramid tablet debossed with “W” (over) “50” on the flat side NDC 0008-1211-14, bottle of 14 tablets in unit-of-use package NDC 0008-1211-30, bottle of 30 tablets in unit-of-use package NDC 0008-1211-01, bottle of 90 tablets in unit-of-use package NDC 0008-1211-50, 10 blisters of 10 (HUD) 100 mg, reddish-orange, square pyramid tablet debossed with “W” (over) “100” on the flat side NDC 0008-1222-14, bottle of 14 tablets in unit-of-use package NDC 0008-1222-30, bottle of 30 tablets in unit-of-use package NDC 0008-1222-01, bottle of 90 tablets in unit-of-use package NDC 0008-1222-50, 10 blisters of 10 (HUD) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .
Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively.
RECENT MAJOR CHANGES
Dosage and Administration ( 2.5 ) 2/2018 Warnings and Precautions ( 5.2 , 5.4 , 5.5 , 5.7 ) 2/2018
8.5 Geriatric Use Of the 4,158 patients in pre-marketing clinical studies with PRISTIQ, 6% were 65 years of age or older.
No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with PRISTIQ [see Adverse Reactions (6.1) ] .
For elderly patients, possible reduced renal clearance of PRISTIQ should be considered when determining dose [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] .
SSRIs and SNRIs, including PRISTIQ, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.9) ] .
DOSAGE FORMS AND STRENGTHS
3 25 mg Tablet: tan, square pyramid tablet debossed with “W” over “25” on the flat side 50 mg Tablet: light pink, square pyramid tablet debossed with “W” over “50” on the flat side 100 mg Tablet: reddish-orange, square pyramid tablet debossed with “W” over “100” on the flat side PRISTIQ extended-release tablets: 25 mg, 50 mg and 100 mg ( 3 ).
Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of desvenlafaxine, respectively ( 3 ).
MECHANISM OF ACTION
12.1 Mechanism of Action The exact mechanism of the antidepressant action of desvenlafaxine is unknown, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake.
Non-clinical studies have shown that desvenlafaxine is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI).
INDICATIONS AND USAGE
1 PRISTIQ is indicated for the treatment of adults with major depressive disorder (MDD) [see Clinical Studies (14) ] .
PRISTIQ is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of adults with major depressive disorder (MDD) ( 1 ).
8.4 Pediatric Use The safety and effectiveness of PRISTIQ have not been established in pediatric patients for the treatment of MDD.
Efficacy was not demonstrated in two adequate and well controlled, 8-week, randomized, double-blind, placebo-controlled, parallel group studies conducted in 587 patients (7 to 17 years of age) for the treatment of MDD.
Antidepressants, such as PRISTIQ, increase the risk of suicidal thoughts and behaviors in pediatric patients [see the Boxed Warning and Warnings and Precautions (5.1) ] .
PRISTIQ was associated with a decrease in body weight in placebo-controlled trials in pediatric patients with MDD.
The incidence of weight loss (≥3.5% of baseline weight) was 22%, 14%, and 7% for patients treated with low dose PRISTIQ, high dose PRISTIQ, and placebo, respectively.
The risks associated with longer term PRISTIQ use were assessed in 6-month, open-label extension studies in pediatric patients (7 to 17 years of age) with MDD.
Pediatric patients (7 to 17 years of age) had mean changes in weight that approximated expected changes, based on data from age- and sex-matched peers.
In clinical trials, when compared to adult patients receiving the same dose of PRISTIQ, exposure to desvenlafaxine was similar in adolescent patients 12 to 17 years of age, and was about 30% higher in pediatric patients 7 to 11 years of age.
Juvenile Animal Studies In a juvenile animal study, male and female rats were treated with desvenlafaxine (75, 225 and 675 mg/kg/day) starting on postnatal day (PND) 22 through 112.
Behavioral deficits (longer time immobile in a motor activity test, longer time swimming in a straight channel test, and lack of habituation in an acoustic startle test) were observed in males and females but were reversed after a recovery period.
A No Adverse Effect Level (NOAEL) was not identified for these deficits.
The Low Adverse Effect Level (LOAEL) was 75 mg/kg/day which was associated with plasma exposure (AUC) twice the levels measured with a pediatric dose of 100 mg/day.
In a second juvenile animal study, male and female rats were administered desvenlafaxine (75, 225 or 675 mg/kg/day) for 8–9 weeks starting on PND 22 and were mated with naïve counterparts.
Delays in sexual maturation and decreased fertility, number of implantation sites and total live embryos were observed in treated females at all doses.
The LOAEL for these findings is 75 mg/kg/day which was associated with an AUC twice the levels measured with a pediatric dose of 100 mg/day.
These findings were reversed at the end of a 4-week recovery period.
The relevance of these findings to humans is not known.
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy.
Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185.
Risk Summary There are no published studies on PRISTIQ in pregnant women; however published epidemiologic studies of pregnant women exposed to venlafaxine, the parent compound, have not reported a clear association with adverse developmental outcomes (see Data ) .
There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including PRISTIQ, during pregnancy ( see Clinical Considerations ).
In reproductive developmental studies in rats and rabbits treated with desvenlafaxine succinate, there was no evidence of teratogenicity at a plasma exposure (AUC) that is up to 19-times (rats) and 0.5-times (rabbits) the exposure at an adult human dose of 100 mg per day.
However, fetotoxicity and pup deaths were observed in rats at 4.5-times the AUC exposure observed with an adult human dose of 100 mg per day.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, showed that women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Maternal Adverse Reactions Exposure to SNRIs in mid to late pregnancy may increase the risk for preeclampsia, and exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage.
Fetal/Neonatal Adverse Reactions Exposure to SNRIs or SSRIs in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.
Monitor neonates who were exposed to PRISTIQ in the third trimester of pregnancy for drug discontinuation syndrome (see Data ).
Data Human Data Published epidemiological studies of pregnant women exposed to the parent compound venlafaxine have not reported a clear association with major birth defects or miscarriage.
Methodological limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders, and confirmatory studies; therefore, these studies cannot establish or exclude any drug-associated risk during pregnancy.
Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy.
One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women [adjusted (adj) RR 1.57, 95% CI 1.29–1.91].
Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg/day and a duration of treatment >30 days.
Another study that assessed venlafaxine exposure in gestational weeks 10–20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg/day.
Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders.
Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage.
One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women [adj RR 2.24 (95% CI 1.69–2.97)].
There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy.
Limitations of this study include possible confounding due to depression severity and other confounders.
Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64–1.76).
The results of this study may be confounded by the effects of depression.
Neonates exposed to SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.
Such complications can arise immediately upon delivery.
Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.
These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.
It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2) ] .
Animal Data When desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no teratogenic effects were observed.
These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5 times (rabbits) the AUC exposure at an adult human dose of 100 mg per day.
However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult human dose of 100 mg per day.
When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and lactation, there was a decrease in pup weights and an increase in pup deaths during the first four days of lactation at the highest dose of 300 mg/kg/day.
The cause of these deaths is not known.
The AUC exposure at the no-effect dose for rat pup mortality was 4.5-times the AUC exposure at an adult human dose of 100 mg per day.
Post-weaning growth and reproductive performance of the progeny were not affected by maternal treatment with desvenlafaxine succinate at exposures 19 times the AUC exposure at an adult human dose of 100 mg per day.
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies.
These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1) ] .
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors.
Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1) ] .
PRISTIQ is not approved for use in pediatric patients [see Use in Specific Populations (8.4) ] .
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning.
Increased the risk of suicidal thoughts and behaviors in children, adolescents and young adults taking antidepressants ( 5.1 ).
Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1 ).
PRISTIQ is not approved for use in pediatric patients ( 8.4 ).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone.
If it occurs, discontinue PRISTIQ and initiate supportive treatment ( 5.2 ).
Elevated Blood Pressure: Control hypertension before initiating treatment.
Monitor blood pressure regularly during treatment ( 5.3 ).
Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk ( 5.4 ).
Angle Closure Glaucoma: Avoid use of antidepressants, including PRISTIQ, in patients with untreated anatomically narrow angles treated ( 5.5 ).
Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder.
Caution patients about risk of activation of mania/hypomania ( 5.6 ).
Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms ( 5.7 ).
Seizure: Can occur.
Use cautiously in patients with seizure disorder ( 5.8 ).
Hyponatremia: Can occur in association with SIADH ( 5.9 ).
Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.10 ).
5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients.
The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric studies.
There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4) , Warnings and Precautions (5.7) ] .
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers .
Prescriptions for PRISTIQ should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder.
It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.
Whether any of the symptoms described above represent such a conversion is unknown.
However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that PRISTIQ is not approved for use in treating bipolar depression.
5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including PRISTIQ, can precipitate serotonin syndrome, a potentially life-threatening condition.
The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.
John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7.1) ] .
Serotonin syndrome can also occur when these drugs are used alone.
Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of PRISTIQ with MAOIs is contraindicated.
In addition, do not initiate PRISTIQ in a patient being treated with MAOIs such as linezolid or intravenous methylene blue.
No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection).
If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PRISTIQ, discontinue PRISTIQ before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7.1) ] .
Monitor all patients taking PRISTIQ for the emergence of serotonin syndrome.
Discontinue treatment with PRISTIQ and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.
If concomitant use of PRISTIQ with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
5.3 Elevated Blood Pressure Patients receiving PRISTIQ should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies [see Adverse Reactions (6.1) ] .
Pre-existing hypertension should be controlled before initiating treatment with PRISTIQ.
Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure.
Cases of elevated blood pressure requiring immediate treatment have been reported with PRISTIQ.
Sustained blood pressure increases could have adverse consequences.
For patients who experience a sustained increase in blood pressure while receiving PRISTIQ, either dose reduction or discontinuation should be considered [see Adverse Reactions (6.1) ] .
5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including PRISTIQ, may increase the risk of bleeding events.
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk.
Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Inform patients about the risk of bleeding associated with the concomitant use of PRISTIQ and antiplatelet agents or anticoagulants.
For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing PRISTIQ.
5.5 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including PRISTIQ may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Avoid use of antidepressants, including PRISTIQ, in patients with untreated anatomically narrow angles.
5.6 Activation of Mania/Hypomania During all MDD phase 2 and phase 3 studies, mania was reported for approximately 0.02% of patients treated with PRISTIQ.
Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants.
As with all antidepressants, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania.
5.7 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.
A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.5) , Adverse Reaction (6.1) ].
5.8 Seizure Cases of seizure have been reported in pre-marketing clinical studies with PRISTIQ.
PRISTIQ has not been systematically evaluated in patients with a seizure disorder.
Patients with a history of seizures were excluded from pre-marketing clinical studies.
PRISTIQ should be prescribed with caution in patients with a seizure disorder.
5.9 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PRISTIQ.
In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Cases with serum sodium lower than 110 mmol/L have been reported.
Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.
Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] .
Discontinuation of PRISTIQ should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls.
Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
5.10 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of PRISTIQ) therapy have been rarely reported.
The possibility of these adverse events should be considered in patients treated with PRISTIQ who present with progressive dyspnea, cough, or chest discomfort.
Such patients should undergo a prompt medical evaluation, and discontinuation of PRISTIQ should be considered.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1) ] .
Concomitant Medication Advise patients taking PRISTIQ not to use concomitantly other products containing desvenlafaxine or venlafaxine.
Healthcare professionals should instruct patients not to take PRISTIQ with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping PRISTIQ before starting an MAOI [see Contraindications (4) ] .
Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of PRISTIQ with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, amphetamines, tryptophan, buspirone, and St.
John’s Wort supplements) [see Warnings and Precautions (5.2) ] .
Elevated Blood Pressure Advise patients that they should have regular monitoring of blood pressure when taking PRISTIQ [see Warnings and Precautions (5.3) ] .
Increased Risk of Bleeding Inform patients about the concomitant use of PRISTIQ with NSAIDs, aspirin, other antiplatelet drugs, warfarin, or other coagulants because the combined use of has been associated with an increased risk of bleeding.
Advise patients to inform their healthcare providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.4) ] .
Activation of Mania/Hypomania Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania [see Warnings and Precautions (5.6) ] .
Discontinuation Advise patients not to abruptly stop taking PRISTIQ without talking first with their healthcare professional.
Patients should be aware that discontinuation effects may occur when stopping PRISTIQ, and a dose of 25 mg per day is available for discontinuing therapy [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ] .
Switching Patients from Other Antidepressants to PRISTIQ Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to PRISTIQ.
Tapering of the initial antidepressant may be necessary to minimize discontinuation symptoms.
Interference with Cognitive and Motor Performance Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that PRISTIQ therapy does not adversely affect their ability to engage in such activities.
Alcohol Advise patients to avoid alcohol while taking PRISTIQ [see Drug Interactions (7.3 ] .
Allergic Reactions Advise patients to notify their physician if they develop allergic phenomena such as rash, hives, swelling, or difficulty breathing.
Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PRISTIQ during pregnancy [see Use in Specific Populations (8.1) ] .
Residual Inert Matrix Tablet Patients receiving PRISTIQ may notice an inert matrix tablet passing in the stool or via colostomy.
Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.
DOSAGE AND ADMINISTRATION
2 Recommended dose: 50 mg once daily with or without food ( 2.1 ).
There was no evidence that doses greater than 50 mg per day confer any additional benefit ( 2.1 ).
The 25 mg per day dose is intended for a gradual reduction in dose when discontinuing treatment or dosing in severe renal and end-stage renal disease patients ( 2.1 ).
Discontinuation: Reduce dose gradually whenever possible ( 2.1 ).
Take tablets whole; do not divide, crush, chew, or dissolve ( 2.1 ).
Moderate renal impairment: Maximum dose 50 mg per day ( 2.2 ).
Severe renal impairment and end-stage renal disease: Maximum dose 25 mg per day or 50 mg every other day ( 2.2 ).
Moderate to severe hepatic impairment: Maximum dose 100 mg per day ( 2.3 ).
2.1 General Instructions for Use The recommended dose for PRISTIQ is 50 mg once daily, with or without food.
The 50 mg dose is both a starting dose and the therapeutic dose.
PRISTIQ should be taken at approximately the same time each day.
Tablets must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.
In clinical studies, doses of 10 mg to 400 mg per day were studied.
In clinical studies, doses of 50 mg to 400 mg per day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg per day and adverse reactions and discontinuations were more frequent at higher doses.
The 25 mg per day dose is intended for a gradual reduction in dose when discontinuing treatment.
When discontinuing therapy, gradual dose reduction is recommended whenever possible to minimize discontinuation symptoms [see Dosage and Administration (2.5) and Warnings and Precautions (5.7) ] .
2.2 Dosage Recommendations for Patients with Renal Impairment The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance [Cl Cr ] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day.
The maximum recommended dose in patients with severe renal impairment (Cl Cr 15 to 29 mL/min, C-G) or end-stage renal disease (ESRD, Cl Cr < 15 mL/min, C-G) is 25 mg every day or 50 mg every other day.
Supplemental doses should not be given to patients after dialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .
2.3 Dosage Recommendations for Patients with Hepatic Impairment The recommended dose in patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) is 50 mg per day.
Dose escalation above 100 mg per day is not recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .
2.4 Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy.
Longer-term efficacy of PRISTIQ (50–400 mg) was established in two maintenance trials [see Clinical Studies (14) ] .
Patients should be periodically reassessed to determine the need for continued treatment.
2.5 Discontinuing PRISTIQ Adverse reactions may occur upon discontinuation of PRISTIQ [see Warnings and Precautions (5.7) ].
Gradually reduce the dosage rather than stopping PRISTIQ abruptly whenever possible.
2.6 Switching Patients From Other Antidepressants to PRISTIQ Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to PRISTIQ.
Tapering of the initial antidepressant may be necessary to minimize discontinuation symptoms.
2.7 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with PRISTIQ.
Conversely, at least 7 days should be allowed after stopping PRISTIQ before starting an MAOI intended to treat psychiatric disorders [ see Contraindications (4) ] .
2.8 Use of PRISTIQ with other MAOIs such as Linezolid or Methylene Blue Do not start PRISTIQ in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome.
In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4) ] .
In some cases, a patient already receiving PRISTIQ therapy may require urgent treatment with linezolid or intravenous methylene blue.
If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, PRISTIQ should be stopped promptly, and linezolid or intravenous methylene blue can be administered.
The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.
Therapy with PRISTIQ may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2) ] .
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with PRISTIQ is unclear.
The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2) ] .